Vaprisol

CLINICAL PHARMACOLOGY

Mechanism of Action

Conivaptan hydrochloride is a dual arginine vasopressin (AVP) antagonist with nanomolar affinity for human V1A and
V2 receptors in vitro. The level of AVP in circulating blood is critical for
the regulation of water and electrolyte balance and is usually elevated in both
euvolemic and hypervolemic hyponatremia. The AVP effect is mediated through V2 receptors,
which are functionally coupled to aquaporin channels in the apical membrane of
the collecting ducts of the kidney. These receptors help to maintain plasma
osmolality within the normal range. The predominant pharmacodynamic effect of
conivaptan hydrochloride in the treatment of hyponatremia is through its V2 antagonism
of AVP in the renal collecting ducts, an effect that results in aquaresis, or
excretion of free water.

Electrophysiology

The effect of VAPRISOL 40 mg IV
and 80 mg IV on the QT interval was evaluated after the first dose (Day 1) and
at the last day during treatment (Day 4) in a randomized, single-blind,
parallel group, placebo- and positive-controlled (moxifloxacin 400 mg IV) study
in healthy male and female volunteers aged 18 to 45 years. Digital ECGs were
obtained at baseline and on Days 1 and 4. Moxifloxacin elicited
placebo-corrected changes from baseline in individualized QT correction (QTcI)
of +7 to +10 msec on Days 1 and 4, respectively, indicating that the study had assay sensitivity. The placebo-corrected changes from baseline in QTcI in the
VAPRISOL 40 mg and 80 mg dose groups on Day 1 were -3.5 msec and -2.9 msec,
respectively, and -2.1 msec for both dose groups on Day 4. The results suggest
that conivaptan has no clinically significant effect on cardiac repolarization.

Pharmacokinetics

The pharmacokinetics of conivaptan have been characterized
in healthy subjects, special populations and patients following both oral and intravenous dosing regimens. The pharmacokinetics of conivaptan following
intravenous infusion (40 mg/day to 80 mg/day) and oral administration are
non-linear, and inhibition by conivaptan of its own metabolism seems to be the
major factor for the non-linearity. The intersubject variability of conivaptan
pharmacokinetics is high (94% CV in CL).

The pharmacokinetics of conivaptan and its metabolites were
characterized in healthy male subjects administered conivaptan hydrochloride as
a 20 mg loading dose (infused over 30 minutes) followed by a continuous
infusion of 40 mg/day for 3 days. Mean Cmax for conivaptan was 619 ng/mL and
occurred at the end of the loading dose. Plasma concentrations reached a
minimum at approximately 12 hours after start of the loading dose, then
gradually increased over the duration of the infusion to a mean concentration
of 188 ng/mL at the end of the infusion. The mean terminal elimination
half-life after conivaptan infusion was 5.0 hours, and the mean clearance was
253.3 mL/min.

In an open-label safety and efficacy study, the
pharmacokinetics of conivaptan were characterized in hypervolemic or euvolemic
hyponatremia patients (ages 20 - 92 years) receiving conivaptan hydrochloride
as a 20 mg loading dose (infused over 30 minutes) followed by a continuous
infusion of 20 or 40 mg/day for 4 days. The median-plasma conivaptan
concentrations are shown in Figure 1. The median (range) elimination half-life
was 5.3 (3.3 - 9.3) or 8.1 (4.1 - 22.5) hours in the 20 mg/day or 40 mg/day
group, respectively, based on data from rich PK sampling.

Distribution

Conivaptan is extensively bound to
human plasma proteins, being 99% bound over the concentration range of
approximately 10 to 1000 ng/mL.

Metabolism and Excretion

CYP3A was identified as the sole
cytochrome P450 isozyme responsible for the metabolism of conivaptan. Four
metabolites have been identified. The pharmacological activity of the
metabolites at V1A and V2 receptors ranged from approximately
3-50% and 50-100% that of conivaptan, respectively. The combined exposure of
the metabolites following intravenous administration of conivaptan is
approximately 7% that of conivaptan and hence, their contribution to the
clinical effect of conivaptan is minimal.

After intravenous (10 mg) or oral
(20 mg) administration of conivaptan hydrochloride in a mass balance study,
approximately 83% of the dose was excreted in feces as total radioactivity and
12% in urine over several days of collection. Over the first 24 hours after
dosing, approximately 1% of the intravenous dose was excreted in urine as
intact conivaptan.

Special Populations

Hepatic Impairment

The systemic exposure to conivaptan is approximately doubled
in subjects with moderate hepatic impairment. No clinically relevant increase
in exposure was observed in subjects with mild hepatic impairment. The impact
of severe hepatic impairment on the exposure to conivaptan has not been studied
[see DOSAGE AND ADMINISTRATION and Use In Specific Populations].

Renal Impairment

Mild and moderate renal impairment (CLcr 30 – 80 mL/min) do
not affect exposure to VAPRISOL to a clinically relevant extent. Use in
patients with severe renal impairment (CLcr < 30 mL/min) is not recommended [see
Use In Specific Populations].

Clinical Studies

Hyponatremia

The effect on serum sodium of VAPRISOL was demonstrated in a double-blind, placebo-controlled, randomized, multicenter study conducted in 84
patients with euvolemic (N=56) or hypervolemic (N=28) hyponatremia (serum
sodium 115 -130 mEq/L) from a variety of underlying causes (malignant or
nonmalignant diseases of the central nervous system, lung, or abdomen;
congestive heart failure; hypertension; myocardial infarction; diabetes;
osteoarthritis; or idiopathic). Study participants were randomized to receive
either placebo IV (N=29), VAPRISOL 40 mg/day IV (N=29), or VAPRISOL 80 mg/day
IV (N=26). Daily fluid intake was restricted to 2 liters. VAPRISOL or placebo
was administered as a continuous infusion following a 30 minute IV loading dose
on the first treatment day and patients were treated for 4 days. Serum or
plasma sodium concentrations were assessed pre-dose (Hour 0) and at 4, 6, 10,
and 24 hours post-dose on all treatment days.

Mean serum sodium concentration was 123.3 mEq/L at study
entry. The mean change in serum sodium concentration from baseline over the
4-day treatment period is shown in Figure 2.

Following treatment with 40 mg/day
of VAPRISOL, the mean change from baseline in serum sodium concentration at the
end of 2 days of treatment with VAPRISOL was 5.3 mEq/L (mean concentration
128.6 mEq/L). At the end of the 4-day treatment period, the mean change from
baseline was 6.5 mEq/L (mean concentration 129.8 mEq/L). In addition, after 2
days and 4 days of treatment with VAPRISOL, 41% (after 2 days) and 69% (after 4
days) of patients achieved a ≥ 6 mEq/L increase in serum sodium
concentration or a normal serum sodium of ≥ 135 mEq/L. Although 80 mg/day
was also studied, it was not significantly more effective than 40 mg/day and
was associated with a higher incidence of infusion site reactions and a higher
rate of discontinuations for adverse events [see ADVERSE REACTIONS].
Additional efficacy data are summarized in Table 2.

Table 2: Efficacy Outcomes of
Treatment with VAPRISOL 40 mg/day

Efficacy Variable

Placebo
N=29

VAPRISOL 40 mg/day
N=29

Day 2‡

Day 4

Day 2‡

Day 4

Baseline adjusted serum Na+ AUC over duration of treatment (mEq•hr/L)

Mean (SD)

6.2 (81.8)

61.4 (242.3)

205.9 (171.6)

500.8 (365.5)

LS Mean ± SE

3.8 ± 26.9

12.9 ± 61.2

205.6 ± 26.6 *

490.9 ± 56.8 *

Number of patients (%) and median event time (h) from first dose of study medication to a confirmed ≥ 4 mEq/L increase from Baseline in serum Na+, [95% CI]

2 (7%)

9 (31%)

22 (76%)

23 (79%)

Not estimable

Not estimable

23.7 *

23.7 *

Not estimable

Not estimable

[10, 2]

[10, 2]

Serum Na+ (mEq/L)

Baseline mean (SD)

124.3 (4.1)

124.3 (4.1)

123.3 (4.7)

123.3 (4.7)

Mean (SD) at end of treatment

124.5 (4.7)

125.8 (4.9)

128.6 (5.9)

129.8 (4.8)

Change from Baseline to end of treatment

Mean change (SD)

0.2 (2.5)

1.5 (4.6)

5.3 (4.4)

6.5 (4.4)

LS Mean change ± SE

0.1 ± 0.7

0.8 ± 0.8

5.2 ± 0.7*

6.3 ± 0.7*

Number (%) of patients who obtained a confirmed ≥ 6 mEq/L increase from Baseline in serum Na+ or a normal serum Na+ concentration ≥ 135 mEq/L during treatment

0 (0)

6 (21%)

12 (41%)*

20 (69%)*

*: P ≤ 0.001 vs placebo
‡: efficacy variables were assessed on Day 2 of a 4-day treatment period

The aquaretic effect of VAPRISOL
is shown in Figure 3. VAPRISOL produced a baseline-corrected cumulative
increase in effective water clearance of over 3800 mL compared to approximately
1300 mL with placebo by Day 4.

The effect on serum sodium of
VAPRISOL (administered as a 20 or 40 mg/day IV continuous infusion for 4 days
following a 30 minute IV infusion of a 20 mg loading dose on the first treatment
day) was also evaluated in an open-label study of 251 patients with euvolemic
or hypervolemic hyponatremia. The results are shown in Table 3.

Table 3: Efficacy Outcomes of
Treatment with VAPRISOL 20 or 40 mg/day

Primary Efficacy Endpoint

20 mg/day
N=37

40 mg/day
N=214

Baseline adjusted serum Na+ AUC over duration of treatment

(mEq•hr/L) Mean (SD)

753.8 (429.9)

689.2 (417.3)

Secondary Efficacy Endpoints

Number of patients (%)

29 (78%)

178 (83%)

and median event time (h) from first dose of study medication to a confirmed ≥ 4 mEq/L increase from Baseline in serum Na+, [95% CI]

23.8[12.0, 36.0]

24.4 [24.0, 35.8]

Total time (h) from first dose of study medication to end of treatment during which patients had a confirmed ≥ 4 mEq/L increase in serum Na+ from Baseline Mean (SD)

60.6 (35.2)

59.5 (33.2)

Serum Na+ (mEq/L)

Baseline mean (SD)

122.5 (5.2)

123.8 (4.6)

Mean (SD) at end of treatment

131.8 (3.9)

132.5 (4.6)

Mean Change (SD) from Baseline to End of Treatment

9.4 (5.3)

8.8 (5.4)

Mean (SD) at Follow-up Day 11

129.9 (6.2)

131.8 (5.8)

Mean Change (SD) from Baseline to Follow-up Day 11

7.1 (8.2)

8.0 (6.5)

Mean (SD) at Follow-up Day 34

134.3 (4.5)

134.3 (5.2)

Mean Change (SD) from Baseline to Follow-up Day 34

11.5 (7.3)

10.7 (6.7)

Number (%) of patients who obtained a confirmed ≥ 6 mEq/L increase from Baseline in serum Na+ or a normal serum Na+ concentration ≥ 135 mEq/L during treatment

26 (70%)

154 (72%)

Heart Failure

The effectiveness of VAPRISOL for
the treatment of congestive heart failure has not been established. In ten
Phase 2/pilot heart failure studies, VAPRISOL did not show statistically
significant improvement for heart failure outcomes, including such measures as
length of hospital stay, changes in categorized physical findings of heart
failure, change in ejection fraction, change in exercise tolerance, change in
functional status, or change in heart failure symptoms, compared to placebo. In
these studies, the changes in the physical findings and heart failure symptoms
were no worse in the VAPRISOL-treated group (N=818) compared to the placebo
group (N=290) [see INDICATIONS AND USAGE].

Last reviewed on RxList: 2/28/2012
This monograph has been modified to include the generic and brand name in many instances.